DESCRIPTION: From the earliest days of the AIDS epidemic, monocytes and macrophages have been shown to be key players in the establishment and maintenance of HIV infection (1). The importance of monocyte/macrophages in all aspects of the infectious process has been extensively documented (2). Most notably, their role in the establishment and maintenance of infection in the central nervous system (CNS) has been fully appreciated (3). Over the last several years, our laboratory has made significant progress towards the development and implementation of humanized mice for HIV research. In particular, we have established critical parameters for the use of bone marrow/liver/thymus (BLT) humanized mice and T cell only mice (ToM) for the analysis of latency and eradication. Specifically, we have established effective antiretroviral therapy (ART) that results in viral suppression, established the development of latently HIV infected T cells, quantitated the frequency of latently infected cells systemically an per tissue, and demonstrated that latency can be disrupted ex-vivo after induction resulting in virus production. Finally, we implemented novel approaches to kill HIV infected T cells that compose the residual active reservoir that persist in vivo despite ART. Through a parallel line of investigation, we have recently implemented a novel animal model that differs from all other existing humanized mouse models used to study HIV in one important fact: it does not contain any human T cells. Instead, in addition to human B cells, it contains a complete complement of myeloid cells including monocytes, macrophages and dendritic cells all of which are important targets for HIV infection, pathogenesis, transmission, persistence and disease progression. The availability of a model in which only the human myeloid-cells present in all tissues including the brain are targets of HIV infection (designated MoM, for myeloid only mice) permits, for the first time, detailed in vivo study of the role of myeloid cells in HIV infection, dissemination, pathogenesis, latency and persistence. As part of this grant we propose to carry out the following Specific Aims: 1) To establish the susceptibility of humanized MoM to HIV-1 infection by macrophage- and T cell-tropic viruses. Hypothesis: Macrophages are sufficient to sustain HIV replication in vivo in the absence of human T cells. MoM can serve as a highly innovative model in which to study in detail the biology and pathogenesis of HIV infection in myeloid cells in vivo. 2) To determine the effect of ART on HIV-1 replication in humanized MoM. A better understanding of the role of myeloid cells in HIV persistence requires the establishment of robust pharmacological interventions capable of efficiently suppressing HIV replication in this compartment. Hypothesis: Highly active triple combination antiretroviral therapy is effective at suppressing HIV replication in macrophages in vivo. 3) To characterize the role of macrophages on the establishment and maintenance of the latent HIV reservoir in the periphery and in the brain of humanized MoM. Hypothesis: Macrophages represent a reservoir of HIV that contributes to HIV persistence in vivo.